Neoadjuvant Opdualag versus Nivolumab for the Treatment of Resectable High-Risk Basal Cell Carcinoma

Inclusion Criteria

• Ability to understand and the willingness to sign a written informed consent document
• Participants must have histologically or cytologically confirmed basal cell carcinoma
• Participants must have HR-BCC as defined by size 20 mm or greater in the head and neck region or 40 mm or greater for the trunk/extremities
• Participants must have surgically resectable BCC that is at increased risk for cosmetic disfigurement, functional defects, poor oncologic control, or anticipated to require skin grafting or free flap reconstruction per investigator assessment
• Participants must have not received immunotherapy for HR-BCC
• Aged 18 years or older
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Absolute neutrophil count ≥ 1,500/mcL
• Platelets ≥ 100,000/mcL
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (except participants with Glibert's syndrome who must have a total bilirubin level of < 3.0 x ULN)
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) ≤ 3 x institutional upper limit of normal (ULN)
• Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) ≤ 3 x institutional upper limit of normal
• Calculated creatinine clearance (CrCl) > 30 mL/min (using the Cockcroft-Gault formula)
• Human immunodeficiency virus (HIV)-infected individuals on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial. Patients must not have had an AIDS defining opportunistic infection within the last year or a current CD4 count < 350 cells/uL
• For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Individuals with a history of hepatitis C virus (HCV) infection must have been treated and cured. For individuals with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Concurrent malignancy (present during screening) requiring treatment or history of prior malignancy active within 2 years prior to randomization (i.e., participants with a history of prior malignancy are eligible if treatment was completed at least 2 years before randomization and the patient has no evidence of disease). Participants with history of prior early stage basal/squamous cell skin cancer or non-invasive or in situ cancers that have undergone definitive treatment at any time are also eligible
• The effects of Opdualag on the on the developing human fetus are unknown * COHORT 1 OPDUALAG: ** A woman of child bearing potential (WOCBP) is eligible to enroll if using a contraceptive method that is highly effective (with a failure rate of < 1% per year), with low user dependency during the intervention period and for the duration of treatment with Opdualag plus 5 half-lives of study treatment for a total of 5 months post-treatment completion and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction for the same time period * COHORT 2 NIVOLUMAB: ** Women who are not of childbearing potential are exempt from contraceptive requirements ** Women participants must have documented proof that they are not of childbearing potential ** Women of child-bearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 24 hours prior to the start of study treatment. An extension up to 72 hours prior to the start of study treatment is permissible in situations where results cannot be obtained within the standard 24-hour window ** Additional requirements for pregnancy testing during and after study intervention ** The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy ** WOCBP must agree to follow instructions for method(s) of contraception ** WOCBP are permitted to use hormonal contraception methods ** A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies: *** Is not a WOCBP OR *** Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of < 1% per year), with low user dependency, during the intervention period and for at least 5 months and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction for the same time period

Exclusion Criteria

• Is currently receiving any other investigational agents
• Has participated in a study of an investigational product and received study treatment or used an investigational device within 4 weeks of the first dose of study treatment
• Hypersensitivity to Opdualag, nivolumab, or any of their excipients
• Presence of untreated (symptomatic) central nervous system (CNS) metastases
• Presence of leptomeningeal metastatic disease
• Treatment with any live/attenuated vaccine within 30 days of first study treatment
• Radiation therapy within 2 weeks prior to first study treatment. Participants must have recovered (i.e., grade ≤ 1 or at baseline) from radiation-related toxicities prior to first study treatment
• Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) within 14 days or other immunosuppressive medications within 30 days of randomization * Note: Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease
• Participants with an active, known, or suspected autoimmune disease * Note: Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
• Prior allogeneic tissue/solid organ transplant
• Severe uncontrolled cardiac disease within 6 months of screening, including but not limited to poorly controlled hypertension, unstable angina, myocardial infarction, congestive heart failure (New York Heart Association class II or greater), pericarditis within the previous 6 months, cerebrovascular accident, or clinically significant uncontrolled cardiac arrhythmias
• Any prior history of myocarditis and/or current diagnosis of myocarditis, regardless of etiology
• Troponin T (TnT) or I (TnI) > 2 x institutional upper limit of normal (ULN) * Participants with TnT or TnI levels between > 1 x to 2 x ULN will be permitted if repeat levels within 24 hours are ≤ 1 x ULN. If TnT or TnI levels are between > 1 x to 2 x ULN within 24 hours, the participant must be evaluated by a cardiologist. When repeat levels within 24 hours are not available, a repeat test should be conducted as soon as possible. If TnT or TnI repeat levels beyond 24 hours are > 2 x ULN, the participant must be evaluated by a cardiologist * After cardiologist evaluation, the participant may be considered for randomization if the investigator assesses a favorable benefit/risk
• Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study treatment administration or that may interfere with the interpretation of study results and, in the judgement of the investigator, would make the patient an inappropriate candidate for the study
• Pregnant women are excluded from this study because Opdualag are immune checkpoint inhibitors with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with Opdualag, breastfeeding should be discontinued if the mother is treated prior to initiating study treatment